title: Necroptosis in immunity and ischemia-reperfusion injury.
abstract: Transplantation is invariably associated with ischemia-reperfusion injury (IRI), inflammation and rejection. Resultant cell death has morphological features of necrosis but programmed cell death has been synonymous with apoptosis until pathways of regulated necrosis (RN) have been described. The best-studied RN pathway, necroptosis, is triggered by perturbation of caspase-8-mediated apoptosis and depends on receptor-interacting protein kinases 1 and 3 (RIPK1/RIPK3) as well as mixed linage kinase domain like to form the necroptosome. The release of cytosolic content and cell death-associated molecular patterns (CDAMPs) can trigger innate and promote adaptive immune responses. Thus, the form of cell death can substantially influence alloimmunity and graft survival. Necroptosis is a key element of IRI, and RIPK1 interference by RN-specific inhibitors such as necrostatin-1 protects from IRI in kidney, heart and brain. Necroptosis may be a general mechanism in response to other forms of inflammatory organ injury, and will likely emerge as a promising target in solid organ transplantation. As second-generation RIPK1 and RIPK3 inhibitors become available, clinical trials for the prevention of delayed graft function and attenuation of allograft rejection-mediated injury will emerge. These efforts will accelerate upon further identification of critical necroptosis-triggering receptor(s).
authors.affiliation: Clinic for Nephrology and Hypertension, Christian-Albrechts University, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Linkermann
authors.forename: M J
authors.initials: MJ
authors.lastname: Hackl
authors.forename: U
authors.initials: U
authors.lastname: Kunzendorf
authors.forename: H
authors.initials: H
authors.lastname: Walczak
authors.forename: S
authors.initials: S
authors.lastname: Krautwald
authors.forename: A M
authors.initials: AM
authors.lastname: Jevnikar
mesh_terms: D000818:Animals; D006801:Humans; D007111:Immunity, Cellular; D009336:Necrosis; D015427:Reperfusion Injury / Q000473:pathology*
keywords: Apoptosis; RIPK1; RIPK3; necroptosis; necrostatin; regulated necrosis